Novel steady state of a microtubule assembly in a confined geometry

We study the steady state of an assembly of microtubules in a confined volume, analogous to the situation inside a cell where the cell boundary forms a natural barrier to growth. We show that the dynamical equations for growing and shrinking microtubules predict the existence of two steady states, with either exponentially decaying or exponentially increasing distribution of microtubule lengths. We identify the regimes in parameter space corresponding to these steady states. In the latter case, the apparent catastrophe frequency near the boundary was found to be significantly larger than that in the interior. Both the exponential distribution of lengths and the increase in the catastrophe frequency near the cell margin is in excellent agreement with recent experimental observations.Comment: 8 pages, submitted to Phys. Rev.

EVALUATION OF ENERGY EFFICIENCY ACTIVITIES SAVINGS FUEL AND ENERGY RESOURCES IN THE METALLURGICAL INDUSTRY

This article discusses the most important areas of measures for energy saving and energy efficiency in aluminum production. The main factors affecting the efficiency of metallurgical industry enterprises are presented.В данной статье рассмотрены важнейшие направления мероприятий по энергосбережению и повышению энергоэффективности в алюминиевом производстве. Представлены основные факторы, влияющие на эффективность работы предприятий металлургической отрасли промышленности

Subaru optical observations of the old pulsar PSR B0950+08

We report the B band optical observations of an old (17.5 Myr) radiopulsar PSR B0950+08 obtained with the Suprime-Cam at the Subaru telescope. We detected a faint object, B=27.07(16). Within our astrometrical accuracy it coincides with the radio position of the pulsar and with the object detected earlier by Pavlov et al. (1996) in UV with the HST/FOC/F130LP. The positional coincidence and spectral properties of the object suggest that it is the optical counterpart of PSR B0950+08. Its flux in the B band is two times higher than one would expect from the suggested earlier Rayleigh-Jeans interpretation of the only available HST observations in the adjacent F130LP band. Based on the B and F130LP photometry of the suggested counterpart and on the available X-ray data we argue in favour of nonthermal origin of the broad-band optical spectrum of PSR B0950+08, as it is observed for the optical emission of the younger, middle-aged pulsars PSR B0656+14 and Geminga. At the same time, the optical efficiency of PSR B0950+08, estimated from its spin-down power and the detected optical flux, is by several orders of magnitude higher than for these pulsars, and comparable with that for the much younger and more energetic Crab pulsar. We cannot exclude the presence of a compact, about 1'', faint pulsar nebula around PSR B0950+08, elongated perpendicular to the vector of its proper motion, unless it is not a projection of a faint extended object on the pulsar position.Comment: 8 pages, LaTeX, aa.cls style, 5 PS figures, submitted to A&A. Image is available in FITS format at http://www.ioffe.rssi.ru/astro/NSG/obs/0950-subar

Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Optimizing Combination Therapies with Existing and Future CML Drugs

Small-molecule inhibitors imatinib, dasatinib and nilotinib have been developed to treat Chromic Myeloid Leukemia (CML). The existence of a triple-cross-resistant mutation, T315I, has been a challenging problem, which can be overcome by finding new inhibitors. Many new compounds active against T315I mutants are now at different stages of development. In this paper we develop an algorithm which can weigh different combination treatment protocols according to their cross-resistance properties, and find the protocols with the highest probability of treatment success. This algorithm also takes into account drug toxicity by minimizing the number of drugs used, and their concentration. Although our methodology is based on a stochastic model of CML microevolution, the algorithm itself does not require measurements of any parameters (such as mutation rates, or division/death rates of cells), and can be used by medical professionals without a mathematical background. For illustration, we apply this algorithm to the mutation data obtained in [1], [2]

COMPARATIVE ANALYSIS OF CLASSICAL NUCLEAR REACTOR KINETICS AND KINETICS OF MARKOV CHAIN FISSION REACTION

Comparison of the classical kinetics of the nuclear reactor with the kinetics of the Markov chain nuclear reaction had established the limits of application of the classical kinetics, depending on the reactivity and the degree of divergence from the kinetics of the Markov chain reaction

Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies

The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type

Nonlinear deterministic equations in biological evolution

We review models of biological evolution in which the population frequency changes deterministically with time. If the population is self-replicating, although the equations for simple prototypes can be linearised, nonlinear equations arise in many complex situations. For sexual populations, even in the simplest setting, the equations are necessarily nonlinear due to the mixing of the parental genetic material. The solutions of such nonlinear equations display interesting features such as multiple equilibria and phase transitions. We mainly discuss those models for which an analytical understanding of such nonlinear equations is available.Comment: Invited review for J. Nonlin. Math. Phy

New Studies of the Pulsar Wind Nebula in the Supernova Remnant CTB 80

We investigated the kinematics of the pulsar wind nebula (PWN) associated with PSR B1951+32 in the old supernova remnant CTB 80 using the Fabry-Perot interferometer of the 6m Special Astrophysical Observatory telescope. In addition to the previously known expansion of the system of bright filaments with a velocity of 100-200km/s, we detected weak high-velocity features in the H-alpha line at least up to velocities of 400-450km/s. We analyzed the morphology of the PWN in the H-alpha, [SII], and [OIII] lines using HST data and discuss its nature. The shape of the central filamentary shell, which is determined by the emission in the [OIII] line and in the radio continuum, is shown to be consistent with the bow-shock model for a significant (about 60 degrees) inclination of the pulsar's velocity vector to the plane of the sky. In this case, the space velocity of the pulsar is twice higher than its tangential velocity, i.e., it reaches ~500 km/s, and PSR B1951+32 is the first pulsar whose line-of-sight velocity (of about 400 km/s) has been estimated from the PWN observations. The shell-like H-alpha-structures outside the bow shock front in the east and the west may be associated with both the pulsar's jets and the pulsar-wind breakthrough due to the layered structure of the extended CTB 80 shell.Comment: to appear in Astronomy Letters, 12 pages, 6 postscript figures, two in colour; for a version with high resolution figures see http://www.sao.ru/hq/grb/team/vkom/CTB80_fine.pd

Ectopic A-lattice seams destabilize microtubules

Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe